EGFR (Epidermal Growth Factor Receptor) is a member of the erbB receptor family, which includes transmembrane protein tyrosine kinase receptors. By binding to its ligand, such as epidermal growth factor (EGF), EGFR can form a homodimer on the cell membrane or form a heterodimer with other receptors in the family, such as erbB2, erbB3, or erbB4. The formation of these dimers can cause the phosphorylation of key tyrosine residues in EGFR cells, thereby activating a number of downstream signaling pathways in cells. These intracellular signaling pathways play an important role in cell proliferation, survival and anti-apoptosis. Disorders of EGFR signal transduction pathways, including increased expression of ligands and receptors, EGFR gene amplification and mutation and the like, can promote malignant transformation of cells and play an important role in tumor cell proliferation, invasion, metastasis and angiogenesis. Therefore, EGFR is a reasonable target for the development of anticancer drugs.
The first generation of small molecule EGFR inhibitors, including gefitinib (Iressa™) and erlotinib (Tarceva™), have shown good efficacy in treatment of lung cancer and have been used as first-line drugs for treating non-small cell lung cancer (NSCLC) associated with EGFR-activated mutation (New England Journal of Medicine (2008) Vol. 358, 1160-74, Biochemical and Biophysical Research Communications (2004) Vol. 319, 1-11).
In contrast to the wild-type (WT) EGFR, the activated mutant-type EGFR (including L858R and delE746_A750 with exon 19 deletion), has lower affinity for adenosine triphosphate (ATP), but has higher affinity for small molecule inhibitors, which leads to increased susceptibility of tumor cells to the first generation of EGFR inhibitors such as gefitinib or erlotinib, thereby achieving a targeted therapy (Science (2004) No. 304, 1497-500; New England Journal of medicine (2004) No. 350, 2129-39).
However, after 10-12 months of treatment with the first generation of small-molecule EGFR inhibitors, resistance to these small molecule inhibitors has been observed in almost all NSCLC patients. The resistance mechanisms include secondary mutations of EGFR, bypass-activation and the like. Thereinto, half of the drug resistance is due to the secondary mutations of T790M, which is a gatekeeper gene residue of EGFR. The secondary mutations reduce the affinity of the drug with the target, thereby producing drug resistance, and resulting in tumor recurrence or disease progression.
In view of the importance and universality of this mutation for drug resistance produced in therapy targeting EGFR of lung cancer, a number of drug research and development companies (Pfizer, BI, AZ, etc.) have attempted to develop second generation small molecule EGFR inhibitors for treating these patients with drug-resistant lung cancer by inhibiting the EGFR-T790M mutant. However, all attempts failed due to poor selectivity. Even if afatinib has been approved by the FDA for the treatment of lung cancer, it was only used in the first-line treatment for patients associated with EGFR-activated mutation. However, afatinib did not show therapeutic efficacy in patients having the EGFR-T790M mutation because afatinib has a stronger inhibitory effect on wild-type EGFR, which causes serious skin and gastrointestinal toxicity, thereby limiting the administration dose.
Therefore, it is necessary to develop third generation small-molecule EGFR inhibitors which can inhibit the EGFR T790M mutant with high selectivity and have no or low activity to wild-type EGFR. Because of this high selectivity, the skin and gastrointestinal damage caused by the inhibition of wild-type EGFR can be greatly decreased and the drug-resistant tumor caused by the secondary mutation of EGFR-T790M can be treated. In addition, it makes sense to maintain the inhibitory activity to EGFR-activated mutant (including EGFR-L858R and delE746_A750 with exon 19 deletion). Due to the lower inhibition of wild-type EGFR, the third generation EGFR inhibitors have better safety than the first generation EGFR inhibitors, and are expected as the first-line therapy in treating NSCLC associated with EGFR-activated mutation, meanwhile, eliminating a small number of EGFR-T790T mutant that may exist in patients with the initial treatment to delay drug resistance.
Lung cancer is a major disease that threatens human health, and the mortality of lung cancer is the leading cause of all malignant tumors. In China, the incidence of lung cancer increases year by year, with nearly 700,000 new cases each year. In Europe and America, lung cancer associated with EGFR-activated mutation accounts for about 10% of all NSCLC; while in China, this ratio is up to 30%. Therefore, China has a larger market for the EGFR target.